Neuronal lesions containing either abnormal pathological tau or abnormal pathological TDP-43 protein characterize frontotemporal lobar degeneration (FTLD). How aggregated, ubiquitinated and phosphorylated TDP-43 protein causes neuronal dysfunction and neurodegeneration is unknown. Likewise, the mechanisms of tau toxicity remain incompletely understood, but hyperphosphorylated, aggregated, and oligomeric tau species exhibit neurotoxicity. This work focuses on extending our previous studies of TDP-43 proteinopathy to complete the molecular genetic dissection of the mechanisms causing neurodegeneration in FTLD-tau and FTLD-TDP. In the previous funding period we showed activation of tau tubulin kinase 1 (TTBK1) stimulates the production of phosphorylated TDP-43, which drives neurodegeneration. We also demonstrated that Calcineurin is the major TDP-43 phosphatase responsible for detoxifying phosphorylated TDP-43. Surprisingly, both TTBK1 and calcineurin play a similar role in the genesis of pathological tau protein in disease. Taken together these findings support the premise of this application that common molecular mechanisms may underpin both TDP-43 and tau pathology in FTLD. The specific aims of this competitive renewal are: 1) Identify genes with protective variants preventing tau or TDP-43 proteinopathy; 2) Conduct comparative analysis of protective genetic variants for impact in molecular mechanisms of neurodegeneration; 3) Assess protective variants for translational potential as therapeutic targets. Completion of the proposed work will enable the development of neuroprotective strategies targeting pathological tau and TDP-43 in FTLD. The experiments proposed here will define new genes and pathways mediating tau and TDP-43 toxicity. The work will also delineate the relationships between the identified genes and pathways to inform development of new therapies for FTLD.